CN101522206A - Therapeutic and/or ameliorating agent for disseminated intravascular coagulation - Google Patents
Therapeutic and/or ameliorating agent for disseminated intravascular coagulation Download PDFInfo
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- CN101522206A CN101522206A CNA2007800368187A CN200780036818A CN101522206A CN 101522206 A CN101522206 A CN 101522206A CN A2007800368187 A CNA2007800368187 A CN A2007800368187A CN 200780036818 A CN200780036818 A CN 200780036818A CN 101522206 A CN101522206 A CN 101522206A
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- thrombomodulin
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- intravascular coagulation
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/7455—Thrombomodulin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
It is an object of the present invention to provide a therapeutically effective agent for therapy and/or improvement of DIC, or a method for treating and/or improving DIC. The present invention provides an agent for therapy and/or improvement of disseminated intravascular coagulation comprising thrombomodulin as an active ingredient, which is administered to antithrombin-reduced patients having a low plasma antithrombin activity of less than 50%.
Description
Technical field
The present invention relates to therapeutic effect higher, be the therapeutic agent and/or the improving agent at disseminated intravascular coagulation of effective ingredient with the thrombomodulin.Further, the present invention relates to select to give the disseminated intravascular coagulation patient's of thrombomodulin method.
Background technology
Disseminated intravascular coagulation (the following DIC that abbreviates as sometimes) is a kind of for the blood coagulation disease, be following disease: owing to the tissue disorder in the various diseases flows out a large amount of blood vessels and solidifies the promotion material, the function of blood coagulation system is extremely hyperfunction, in the blood vessel of whole body, produce little thrombosis, stop up little blood vessel; Simultaneously necessary platelet of control over bleeding or thrombin are consumed and the deficiency that becomes, the result causes disorders of hemostasis.Among the DIC, thrombin is accumulated in the blood capillary of kidney, lung and is produced ischemia, causes circulatory disturbance and shock more.Rapid breathing, dyspnea, tachycardia, bradycardia, extremity cold, oliguria, spasm etc. may appear thus, and might be under some situation owing to shock is died suddenly.Simultaneously, because thrombin and hematoblastic consumption produce bleeding tendency, cause purpura, petechial hemorrhage, spitting of blood, haematemesis, hematuria, hemafecia or the epistaxis etc. of skin.As the DIC therapeutic agent, use heparin, antithrombase (be also referred to as Antithrombin III sometimes, below abbreviate AT or ATIII sometimes as) etc.
On the other hand, known thrombomodulin is following material, and it combines specifically with thrombin, significantly promotes the effect of the PROTEIN C activation capacity of thrombin when having the blood coagulation activity of Trombin inhibiting, and known its has powerful blood coagulation inhibitory action.Known thrombomodulin prolongs the time of carrying out blood coagulation by thrombin, suppresses the platelet aggregation that is undertaken by thrombin.PROTEIN C is the protein of the vitamin k-dependent that plays an important role in hemostatic system, it becomes the activated form PROTEIN C by effect activation of thrombin.Known this activated form PROTEIN C makes the active form accelerin of the blood coagulation system factor and active form VIII factor inactivation in vivo, and the generation relevant (non-patent literature 1) of activated form PROTEIN C and the plasminogen activator with thrombolytic effect.Therefore, thrombomodulin promotes the activation of the PROTEIN C of being undertaken by this thrombin, as anticoagulant or thrombolytic agent is useful, and also having and closing the explanation thrombomodulin is effective zooperal report (non-patent literature 2) to being attended by the hyperfunction treatment of diseases of blood coagulation, preventing.
In the past, thrombomodulin was found acquisition as the glycoprotein of expressing on the vascular endothelial cell with the various animal kinds headed by the people, successfully clone then.Promptly, use engineered method, clone by the gene of in people's lung cDNA storehouse the human thrombomodulin that contains signal peptide being regulated amyloid protein precursor, then the full gene sequence of thrombomodulin is resolved, separate the aminoacid sequence (patent documentation 1) of understanding 575 residues that contain signal peptide (enumerating 18 amino acid residues usually).The cut sophisticated thrombomodulin of known signal peptide is from N-terminal one side of its sophisticated peptide, by (the 1st～226 in N-terminal zone; Think that the position when signal peptide is 18 amino acid residues represents, below identical), zone (the 227th～462) with 6 EGF spline structures, O type sugar chain additional areas (the 463rd～498), striding these 5 zones of diaphragm area (the 499th～521) and Cytoplasm inner region (the 522nd～557) constitutes, and as having an active part identical (being minimum activity unit) with the thrombomodulin of total length, in the zone with 6 EGF spline structures mainly by from N-terminal one side the 4th, 5, the part (non-patent literature 3) that 6 EGF spline structure forms.
The thrombomodulin of total length must add surfactant if nextly be not difficult to dissolving in existing of surfactant as preparation, and is relative therewith, even exist a kind of surfactant that do not exist also can smooth dissolved soluble thrombomodulin.Soluble thrombomodulin is prepared into and does not contain part or all of striding diaphragm area at least and get final product, for example, confirm only (promptly by these 3 zones of N-terminal zone, zone and O type sugar chain additional areas with 6 EGF spline structures, the zone that is formed by the 19th～516 aminoacid sequence of serial number 9) soluble thrombomodulin that forms can obtain by using recombinant technique, and this recombinant soluble thrombomodulin has the activity (patent documentation 1) of natural thrombomodulin.The example of soluble thrombomodulin as other has some reports (patent documentation 2～9).In addition, as natural type, enumerated (patent documentations 10,11) such as soluble thrombomodulins that derive from Urina Hominis.
By the way, in gene, in a lot of examples, confirming, variation by nature or the variation when obtaining, also found multifarious variation in the mankind, the 473rd the aminoacid that has confirmed at present the human thrombomodulin adjusting amyloid protein precursor that the aminoacid sequence by above-mentioned 575 residues forms is the sequence of Val and is the sequence of Ala.In this amino acid whose base sequence of coding, the 1418th makes a variation respectively is T and C (non-patent literature 4).But,, can judge that both are identical in fact not having difference fully aspect active and the rerum natura.
Have report to point out, thrombomodulin is effective (non-patent literature 5) in the treatment of DIC.Purposes as thrombomodulin, except above-mentioned, for example, expectation is used for function sexual disorders, the complication of organ transplantation, angina pectoris, transient ischemic attack, hypertensive state of pregnancy, diabetes, liver VOD (the Liver veno-occlusive disease of acute coronary syndrome (ACS), thrombosis, peripheral vessel obliterans, Arteriosclerosis obliterans, vasculitis, operation on heart secondary; Occlusion of hepatic vein disease after acute severe hepatitis or the bone marrow transplantation), deep vein thrombosis (DVT; Deepvenous thrombosis) etc. and in the treatment of diseases of septicemia or adult respiratory distress syndrome (ARDS) and the prevention.
Patent documentation 1: Japanese kokai publication sho 64-6219 communique
Patent documentation 2: Japanese kokai publication hei 2-255699 communique
Patent documentation 3: Japanese kokai publication hei 3-133380 communique
Patent documentation 4: Japanese kokai publication hei 3-259084 communique
Patent documentation 5: Japanese kokai publication hei 4-210700 communique
Patent documentation 6: Japanese kokai publication hei 5-213998 communique
Patent documentation 7:WO92/00325 communique
Patent documentation 8:WO92/03149 communique
Patent documentation 9:WO93/15755 communique
Patent documentation 10: Japanese kokai publication hei 3-86900 communique
Patent documentation 11: Japanese kokai publication hei 3-218399 communique
Non-patent literature 1: Suzuki is grand to be controlled, medical science あ ゆ body (medical science progress), the 125th volume, 901 pages (nineteen eighty-three)
Non-patent literature 2:K.Gomi etc., Blood75.1396-1399 (1990)
Non-patent literature 3:M.Zushi etc., J.Biol.Chem., 246,10351-10353 (1989)
Non-patent literature 4:D.Z.Wen etc., Biochemistry, 26,4350-4357 (1987)
Non-patent literature 5:S.M.Bates etc., Br.J.of Pharmacol., 144,1017-1028 (2005)
Summary of the invention
The DIC therapeutic agent and/or the improving agent that provide therapeutic effect higher or the Therapeutic Method of DIC and/or improvement method are provided problem of the present invention.Another problem of the present invention is to provide the disseminated intravascular coagulation patient's that selection should give thrombomodulin method.
As treatment and/or the improvement of DIC, implement to utilize the anticoagulant therapy of anticoagulant usually or implement replenishing of Platelet Concentrate, FFP.Because the virtual condition of DIC is the overactivity of blood coagulation system, therefore its anticoagulant therapy that suppresses is carried out widely with at the treatment of underlying diseases is parallel.In the treatment and/or improvement of DIC, use heparin and/or AT preparation usually mostly.Owing to think that the blood coagulation resisting function of heparin is (the Maierus PW that expresses by the thrombin inhibition speed of remarkable promotion AT, Tollefsen DM. " the solid medicine of anticoagulant, Actosolv お I び antiplatelet drug (anticoagulant, thrombolytic and antiplatelet drug) " In: high folding repaiies two, Feitian English minister, the clear discipline in red pond is compiled, Gourde(G) Man Jierman pharmacology book, the 10th edition, Tokyo, wide river bookstore, 2003.p1937-63), therefore higher for AT activity value in the blood plasma, for example be that about 80% patient uses heparin (Gang Dao grinds two works " broadcasting many Viscera of Seed IC syndrome と device not complete (disseminated intravascular coagulation and MOFE) ", medical Journal society).In addition, for the AT activity value in the blood plasma is the patient below about 70% for example, can enumerate the AT preparation as representational medicine (Anthrobin P and Neuart additional disclosure book: usage and consumption), the main employing by the AT activity value in the raising blood plasma promotes blood coagulation resisting function to realize the method for treatment and/or the improvement of DIC.In addition, also can and use heparin as required this moment.
So, in order to treat and/or to improve DIC, preferably replenish so that the AT activity value in DIC patient's the blood plasma is remained on more than 70% at least, think in addition and improve AT activity value in the blood plasma in treatment and/or to improve aspect the DIC be general knowledge, in this case, the inventor unexpectedly confirms thrombomodulin and has higher effective for AT activity value in the blood plasma on the contrary less than the low patient of AT activity value in 50% such blood plasma, thereby finishes the present invention.Its result, even estimate in few, the AT activity value is less than finding high effect among the low DIC patient of 50% such activity value in blood plasma, this is the fortuitous event that those skilled in the art can not expect.
Suppose if give AT preparation, the AT preparation that then gives is the preparation that raw material forms for the human blood with preciousness, in addition, can not get rid of fully owing to the danger (Anthrobin P and the Neuart additional disclosure book: application notice) that with the human blood are the infectious disease transmission that causes of raw material, thereby existence is worried, further also have the problem of AT, but the present invention can provide preferred medicine or DIC therapeutic agent and/or the improving agent that addresses these problems as the Blood Preparations costliness.
That is,, can enumerate following scheme as the present invention.
[1] a kind of therapeutic agent of disseminated intravascular coagulation and/or improving agent, it is to be the medicine of effective ingredient with the thrombomodulin, and the antithrombin activity value that this medicine is used for being applied to blood plasma is less than 50% disseminated intravascular coagulation patient;
[2] therapeutic agent and/or the improving agent of above-mentioned [1] described disseminated intravascular coagulation, wherein, this thrombomodulin is a soluble thrombomodulin;
[3] therapeutic agent and/or the improving agent of above-mentioned [1] or [2] described disseminated intravascular coagulation, wherein, this thrombomodulin is the peptide that is obtained by transformant, and described transformant is to prepare in host cell by the DNA transfection with the aminoacid sequence of record in coded sequence numbers 1,3,5,7,9 or the serial number 11;
The therapeutic agent and/or the improving agent of [3-2] above-mentioned [1] or [2] described disseminated intravascular coagulation, wherein, this thrombomodulin is the peptide that is obtained by transformant, and described transformant is to prepare in host cell by the DNA transfection with the aminoacid sequence of record in coded sequence number 1 or the serial number 3;
The therapeutic agent and/or the improving agent of [3-3] above-mentioned [1] or [2] described disseminated intravascular coagulation, wherein, this thrombomodulin is the peptide that is obtained by transformant, and described transformant is to prepare in host cell by the DNA transfection with the aminoacid sequence of record in coded sequence numbers 5 or the serial number 7;
The therapeutic agent and/or the improving agent of [3-4] above-mentioned [1] or [2] described disseminated intravascular coagulation, wherein, this thrombomodulin is the peptide that is obtained by transformant, and described transformant is to prepare in host cell by the DNA transfection with the aminoacid sequence of record in coded sequence numbers 9 or the serial number 11;
[4] therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in above-mentioned [1], [2] or [3-2], wherein, this thrombomodulin is peptide with serial number 1 or serial number 3 sequence of the 19th～132 in separately, has the identical series of variation of above-mentioned sequence and have in active peptide of thrombomodulin or their mixture any one;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [4-2] above-mentioned [1], [2] or [3-2], wherein, this thrombomodulin is to have the peptide of serial number 1 or serial number 3 the 19th～132 sequence in separately or have the identical series of variation of above-mentioned sequence and have the active peptide of thrombomodulin;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [4-3] above-mentioned [1], [2] or [3-2], wherein, this thrombomodulin is the peptide with serial number 1 or serial number 3 sequence of the 19th～132 in separately;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [4-4] above-mentioned [1], [2] or [3-2], wherein, this thrombomodulin is peptide with sequence of serial number 1 or serial number 3 in separately the 19th～132 or the 17th～132, has the identical series of variation of above-mentioned sequence and have in active peptide of thrombomodulin or their mixture any one;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [4-5] above-mentioned [1], [2] or [3-2], wherein, this thrombomodulin is to have serial number 1 or serial number 3 in separately the 19th～132 or the 17th～132 's peptide of sequence or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [4-6] above-mentioned [1], [2] or [3-2], wherein, this thrombomodulin is to have in the serial number 1 the 19th～132 or the 17th～132 's peptide of sequence or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [4-7] above-mentioned [1], [2] or [3-2], wherein, this thrombomodulin is to have in the serial number 3 the 19th～132 or the 17th～132 's peptide of sequence or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [4-8] above-mentioned [1], [2] or [3-2], wherein, this thrombomodulin is the peptide that forms of the sequence by the 19th～132 in the serial number 1 or the 17th～132 or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [4-9] above-mentioned [1], [2] or [3-2], wherein, this thrombomodulin is the peptide that forms of the sequence by the 19th～132 in the serial number 3 or the 17th～132 or their mixture;
[5] therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in above-mentioned [1], [2] or [3-3], wherein, this thrombomodulin is peptide with serial number 5 or serial number 7 sequence of the 19th～480 in separately, has the identical series of variation of above-mentioned sequence and have in active peptide of thrombomodulin or their mixture any one;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [5-2] above-mentioned [1], [2] or [3-3], wherein, this thrombomodulin is to have the peptide of serial number 5 or serial number 7 the 19th～480 sequence in separately or have the identical series of variation of above-mentioned sequence and have the active peptide of thrombomodulin;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [5-3] above-mentioned [1], [2] or [3-3], wherein, this thrombomodulin is the peptide with serial number 5 or serial number 7 sequence of the 19th～480 in separately;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [5-4] above-mentioned [1], [2] or [3-3], wherein, this thrombomodulin is peptide with sequence of serial number 5 or serial number 7 in separately the 19th～480 or the 17th～480, has the identical series of variation of above-mentioned sequence and have in active peptide of thrombomodulin or their mixture any one;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [5-5] above-mentioned [1], [2] or [3-3], wherein, this thrombomodulin is to have serial number 5 or serial number 7 in separately the 19th～480 or the 17th～480 's peptide of sequence or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [5-6] above-mentioned [1], [2] or [3-3], wherein, this thrombomodulin is to have in the serial number 5 the 19th～480 or the 17th～480 's peptide of sequence or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [5-7] above-mentioned [1], [2] or [3-3], wherein, this thrombomodulin is to have in the serial number 7 the 19th～480 or the 17th～480 's peptide of sequence or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [5-8] above-mentioned [1], [2] or [3-3], wherein, this thrombomodulin is the peptide that forms of the sequence by the 19th～480 in the serial number 5 or the 17th～480 or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [5-9] above-mentioned [1], [2] or [3-3], wherein, this thrombomodulin is the peptide that forms of the sequence by the 19th～480 in the serial number 7 or the 17th～480 or their mixture;
[6] therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide with serial number 9 or serial number 11 sequence of the 19th～516 in separately; Have in the aminoacid sequence of above-mentioned peptide and replace, lack or added one or more amino acid whose aminoacid sequence and had the active peptide of thrombomodulin; Or in their mixture any one;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-2] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide with serial number 9 or serial number 11 sequence of the 19th～516 in separately; Or have in the aminoacid sequence of above-mentioned peptide and replace, lack or added one or more amino acid whose aminoacid sequence and had the active peptide of thrombomodulin;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-3] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide with serial number 9 or serial number 11 sequence of the 19th～516 in separately;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-4] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide with sequence of serial number 9 or serial number 11 in separately the 19th～516, the 19th～515, the 17th～516 or the 17th～515; Have in the aminoacid sequence of above-mentioned peptide and replace, lack or added one or more amino acid whose aminoacid sequence and had the active peptide of thrombomodulin; Or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-5] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide with sequence of serial number 9 or serial number 11 in separately the 19th～516, the 19th～515, the 17th～516 or the 17th～515; Or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-6] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide with sequence of in the serial number 9 the 19th～516, the 19th～515, the 17th～516 or the 17th～515; Or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-7] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide with sequence of in the serial number 11 the 19th～516, the 19th～515, the 17th～516 or the 17th～515; Or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-8] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide that the sequence by the 19th～516 in the serial number 9, the 19th～515, the 17th～516 or the 17th～515 forms; Or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-9] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide that the sequence by the 19th～516 in the serial number 9, the 19th～515, the 17th～516 or the 17th～515 forms;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-10] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide that the sequence by the 19th～516 in the serial number 11, the 19th～515, the 17th～516 or the 17th～515 forms; Or their mixture;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [6-11] above-mentioned [1], [2] or [3-4], wherein, this thrombomodulin is the peptide that the sequence by the 19th～516 in the serial number 11, the 19th～515, the 17th～516 or the 17th～515 forms;
[7] therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation among above-mentioned [1]～[6-11], wherein, the disseminated intravascular coagulation patient is that the antithrombin activity value in the blood plasma is the patient below 40%;
Need to prove that the item No. of quoting represents by scope as above-mentioned [1]～[6-11], when in this scope, disposing the item of branches such as having [6-2] number, refer to the item of also quoting branches such as having [6-2] number.Below also identical therewith.
[8] therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in above-mentioned [1]～[7], wherein, the therapeutic agent of disseminated intravascular coagulation and/or improving agent are non-oral administration agent;
[9] therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in above-mentioned [1]～[8], wherein, the therapeutic agent of disseminated intravascular coagulation and/or improving agent are the intravenous administration agent;
[10] therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in above-mentioned [1]～[9] is characterized in that, every day with the dosage of 0.02～0.08mg/kg at 4 hours with interior lasting intravenous drip;
[11] therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in above-mentioned [1]～[10] is characterized in that, its not with the antithrombase combination medicine-feeding;
[12] therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in above-mentioned [1]～[11], wherein, disseminated intravascular coagulation is to come from the hemopoietic system malignant tumor or come from the disseminated intravascular coagulation that infects disease;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [12-1] above-mentioned [1]～[11], wherein, disseminated intravascular coagulation is the disseminated intravascular coagulation that comes from the hemopoietic system malignant tumor;
The therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation in [12-2] above-mentioned [1]～[11], wherein, disseminated intravascular coagulation is to come from the disseminated intravascular coagulation that infects disease;
[12-3] a kind of medicine, it is the medicine that is used to reduce the dead probability of the human patients of suffering from disseminated intravascular coagulation, wherein, this medicine is an effective ingredient with the thrombomodulin, is used for being applied to blood plasma antithrombin activity value less than 50% disseminated intravascular coagulation patient;
The described medicine of [12-4] above-mentioned [12-3], wherein, thrombomodulin is any described peptide among above-mentioned [1]～[6-11];
The described medicine of [12-5] above-mentioned [12-3], it has any described feature among above-mentioned [1]～[12-2];
[13] a kind of system of selection, it is the method that selection should give the disseminated intravascular coagulation patient of thrombomodulin, this method comprises the steps: to measure the antithrombin activity value in disseminated intravascular coagulation patient's the blood plasma, select this antithrombin activity value less than 50% disseminated intravascular coagulation patient, judge that this patient is the disseminated intravascular coagulation patient that should give thrombomodulin;
The described selection in [13-2] above-mentioned [13] should give the disseminated intravascular coagulation patient's of thrombomodulin method, and wherein, thrombomodulin is any described peptide among above-mentioned [1]～[6-11];
The therapeutic agent and/or the improving agent of [13-3] a kind of disseminated intravascular coagulation, it is to be the medicine of effective ingredient with the thrombomodulin, and this medicine is used for being applied to the disseminated intravascular coagulation patient after the antithrombin activity value of measuring blood plasma;
The therapeutic agent and/or the improving agent of [13-4] a kind of disseminated intravascular coagulation, it is to be the medicine of effective ingredient with the thrombomodulin, and this medicine is used for being applied to the disseminated intravascular coagulation patient under less than 50% situation measuring the antithrombin activity value of blood plasma, this antithrombin activity value;
[14] a kind of Therapeutic Method of disseminated intravascular coagulation and/or improvement method, it comprises the step that the antithrombin activity value in the blood plasma is given thrombomodulin less than 50% disseminated intravascular coagulation patient;
[15] above-mentioned [14] described method, wherein, this thrombomodulin is a soluble thrombomodulin;
[16] above-mentioned [14] or [15] described method, wherein, this thrombomodulin is the peptide that is obtained by transformant, and described transformant is to prepare in host cell by the DNA transfection with the aminoacid sequence of record in coded sequence numbers 1,3,5,7,9 or the serial number 11;
[16-2] above-mentioned [14] or [15] described method, wherein, this thrombomodulin is the peptide that is obtained by transformant, and described transformant is to prepare in host cell by the DNA transfection with the aminoacid sequence of record in coded sequence number 1 or the serial number 3;
[16-3] above-mentioned [14] or [15] described method, wherein, this thrombomodulin is the peptide that is obtained by transformant, and described transformant is to prepare in host cell by the DNA transfection with the aminoacid sequence of record in coded sequence numbers 5 or the serial number 7;
[16-4] above-mentioned [14] or [15] described method, wherein, this thrombomodulin is the peptide that is obtained by transformant, and described transformant is to prepare in host cell by the DNA transfection with the aminoacid sequence of record in coded sequence numbers 9 or the serial number 11;
[17] any described method in above-mentioned [14], [15] or [16-2], wherein, this thrombomodulin is peptide with serial number 1 or serial number 3 sequence of the 19th～132 in separately, has the identical series of variation of above-mentioned sequence and have in active peptide of thrombomodulin or their mixture any one;
Any described method in [17-2] above-mentioned [14], [15] or [16-2], wherein, this thrombomodulin is to have the peptide of serial number 1 or serial number 3 the 19th～132 sequence in separately or have the identical series of variation of above-mentioned sequence and have the active peptide of thrombomodulin;
Any described method in [17-3] above-mentioned [14], [15] or [16-2], wherein, this thrombomodulin is the peptide with serial number 1 or serial number 3 sequence of the 19th～132 in separately;
Any described method in [17-4] above-mentioned [14], [15] or [16-2], wherein, this thrombomodulin is peptide with sequence of serial number 1 or serial number 3 in separately the 19th～132 or the 17th～132, has the identical series of variation of above-mentioned sequence and have in active peptide of thrombomodulin or their mixture any one;
Any described method in [17-5] above-mentioned [14], [15] or [16-2], wherein, this thrombomodulin is to have serial number 1 or serial number 3 in separately the 19th～132 or the 17th～132 's peptide of sequence or their mixture;
Any described method in [17-6] above-mentioned [14], [15] or [16-2], wherein, this thrombomodulin is to have in the serial number 1 the 19th～132 or the 17th～132 's peptide of sequence or their mixture;
Any described method in [17-7] above-mentioned [14], [15] or [16-2], wherein, this thrombomodulin is to have in the serial number 3 the 19th～132 or the 17th～132 's peptide of sequence or their mixture;
Any described method in [17-8] above-mentioned [14], [15] or [16-2], wherein, this thrombomodulin is the peptide that forms of the sequence by the 19th～132 in the serial number 1 or the 17th～132 or their mixture;
Any described method in [17-9] above-mentioned [14], [15] or [16-2], wherein, this thrombomodulin is the peptide that forms of the sequence by the 19th～132 in the serial number 3 or the 17th～132 or their mixture;
[18] any described method in above-mentioned [14], [15] or [16-3], wherein, this thrombomodulin is peptide with serial number 5 or serial number 7 sequence of the 19th～480 in separately, has the identical series of variation of above-mentioned sequence and have in active peptide of thrombomodulin or their mixture any one;
Any described method in [18-2] above-mentioned [14], [15] or [16-3], wherein, this thrombomodulin is to have the peptide of serial number 5 or serial number 7 the 19th～480 sequence in separately or have the identical series of variation of above-mentioned sequence and have the active peptide of thrombomodulin;
Any described method in [18-3] above-mentioned [14], [15] or [16-3], wherein, this thrombomodulin is the peptide with serial number 5 or serial number 7 sequence of the 19th～480 in separately;
Any described method in [18-4] above-mentioned [14], [15] or [16-3], wherein, this thrombomodulin is peptide with sequence of serial number 5 or serial number 7 in separately the 19th～480 or the 17th～480, has the identical series of variation of above-mentioned sequence and have in active peptide of thrombomodulin or their mixture any one;
Any described method in [18-5] above-mentioned [14], [15] or [16-3], wherein, this thrombomodulin is to have serial number 5 or serial number 7 in separately the 19th～480 or the 17th～480 's peptide of sequence or their mixture;
Any described method in [18-6] above-mentioned [14], [15] or [16-3], wherein, this thrombomodulin is to have in the serial number 5 the 19th～480 or the 17th～480 's peptide of sequence or their mixture;
Any described method in [18-7] above-mentioned [14], [15] or [16-3], wherein, this thrombomodulin is to have in the serial number 7 the 19th～480 or the 17th～480 's peptide of sequence or their mixture;
Any described method in [18-8] above-mentioned [14], [15] or [16-3], wherein, this thrombomodulin is the peptide that forms of the sequence by the 19th～480 in the serial number 5 or the 17th～480 or their mixture;
Any described method in [18-9] above-mentioned [14], [15] or [16-3], wherein, this thrombomodulin is the peptide that forms of the sequence by the 19th～480 in the serial number 5 or the 17th～480 or their mixture;
[19] any described method in above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is peptide with serial number 9 or serial number 11 sequence of the 19th～516 in separately, has the identical series of variation of above-mentioned sequence and have in active peptide of thrombomodulin or their mixture any one;
Any described method in [19-2] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is to have the peptide of serial number 9 or serial number 11 the 19th～516 sequence in separately or have the identical series of variation of above-mentioned sequence and have the active peptide of thrombomodulin;
Any described method in [19-3] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is the peptide with serial number 9 or serial number 11 sequence of the 19th～516 in separately;
Any described method in [19-4] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is the peptide with sequence of serial number 9 or serial number 11 in separately the 19th～516, the 19th～515, the 17th～516 or the 17th～515; Have the identical series of variation of above-mentioned sequence and have the active peptide of thrombomodulin; Or in their mixture any one;
Any described method in [19-5] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is the peptide with sequence of serial number 9 or serial number 11 in separately the 19th～516, the 19th～515, the 17th～516 or the 17th～515; Or their mixture;
Any described method in [19-6] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is the peptide with sequence of in the serial number 9 the 19th～516, the 19th～515, the 17th～516 or the 17th～515; Or their mixture;
Any described method in [19-7] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is the peptide with sequence of in the serial number 11 the 19th～516, the 19th～515, the 17th～516 or the 17th～515; Or their mixture;
Any described method in [19-8] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is the peptide that the sequence by the 19th～516 in the serial number 9, the 19th～515, the 17th～516 or the 17th～515 forms; Or their mixture;
Any described method in [19-9] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is the peptide that the sequence by the 19th～516 in the serial number 9, the 19th～515, the 17th～516 or the 17th～515 forms;
Any described method in [19-10] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is the peptide that the sequence by the 19th～516 in the serial number 11, the 19th～515, the 17th～516 or the 17th～515 forms; Or their mixture;
Any described method in [19-11] above-mentioned [14], [15] or [16-4], wherein, this thrombomodulin is the peptide that the sequence by the 19th～516 in the serial number 11, the 19th～515, the 17th～516 or the 17th～515 forms;
[20] any described method among above-mentioned [14]～[19-11] wherein, is that disseminated intravascular coagulation patient below 40% gives thrombomodulin to the antithrombin activity value in the blood plasma;
[21] any described method in above-mentioned [14]～[20], wherein, non-orally give thrombomodulin;
[22] any described method in above-mentioned [14]～[21], wherein, intravenous gives thrombomodulin;
[23] any described method in above-mentioned [14]～[22], wherein, every day with the dosage of 0.02～0.08mg/kg at 4 hours with interior lasting intravenous drip thrombomodulin;
[24] any described method in above-mentioned [14]～[23] is characterized in that, thrombomodulin not with the antithrombase combination medicine-feeding;
[25] any described method in above-mentioned [14]～[24], wherein, disseminated intravascular coagulation is to come from the hemopoietic system malignant tumor or come from the disseminated intravascular coagulation that infects disease;
Any described method in [25-1] above-mentioned [14]～[24], wherein, disseminated intravascular coagulation is the disseminated intravascular coagulation that comes from the hemopoietic system malignant tumor;
Any described method in [25-2] above-mentioned [14]～[24], wherein, disseminated intravascular coagulation is to come from the disseminated intravascular coagulation that infects disease;
[26] a kind of method, it is the method that is used to reduce the dead probability of the human patients of suffering from disseminated intravascular coagulation, in this method, thrombomodulin is applied to antithrombin activity value in the blood plasma less than 50% disseminated intravascular coagulation patient;
The described method in [26-2] above-mentioned [26], wherein, thrombomodulin is any described peptide among above-mentioned [1]～[6-11];
[26-3] a kind of medication, its [26] described method that is above-mentioned has any described feature among above-mentioned [1]～[25-2];
[27] a kind of Therapeutic Method of disseminated intravascular coagulation and/or improvement method, it is included in the step that thrombomodulin is applied to after the antithrombin activity value of measuring in the blood plasma disseminated intravascular coagulation patient;
Therapeutic Method of [27-2] a kind of disseminated intravascular coagulation and/or improvement method, it comprises the steps: to measure the antithrombin activity value in the blood plasma, this antithrombin activity value was applied to the disseminated intravascular coagulation patient less than 50% o'clock with thrombomodulin.
The preparation that contains thrombomodulin of the application of the invention can (preferably under situation about not being used in combination with AT) be treated effectively and/or is improved AT activity value in the blood plasma less than 50% DIC patient's symptom.
The specific embodiment
Below, the present invention is carried out specific description.
According to the present invention, the therapeutic agent and/or the improving agent of a kind of disseminated intravascular coagulation (DIC) are provided, it is to be the medicine of effective ingredient with the thrombomodulin, and the antithrombin activity value that this medicine is used for being applied to blood plasma is less than 50% disseminated intravascular coagulation patient.
That is, the therapeutic agent of disseminated intravascular coagulation of the present invention and/or improving agent are that antithrombin activity value in the blood plasma is less than the therapeutic agent and/or the improving agent of 50% disseminated intravascular coagulation patient's disseminated intravascular coagulation.
In addition, the present invention is provided for reducing the medicine of the dead probability of the human patients of suffering from disseminated intravascular coagulation equally.
As treatment and/or the improvement of DIC, for example can enumerate " preventing " and, also can enumerate " preventing " in addition as one of preferred effect as preferred effect because the deterioration of the patient's that DIC causes general body state because the patient's that DIC causes death.
DIC is following disease or syndrome: owing to the tissue disorder in the various diseases flows out a large amount of blood vessels and solidifies the promotion material, the function of blood coagulation system is extremely hyperfunction, produces little thrombosis (forming small thrombosis) in the blood vessel of whole body, stops up little blood vessel; Simultaneously necessary platelet of control over bleeding or thrombin are consumed and the deficiency that becomes, the result causes that hemostasis is unusual.Specifically, owing to form the blood vessel inner fibrin, find because expendable blood coagulation fibrinolytic obstacle causes bleeding symptom or cause the organ failure symptom owing to form microthrombus.DIC is called as disseminated intravascular coagulation or general property intravascular coagulation syndrome sometimes.
In disease based on malignant tumor such as hemopoietic system malignant tumor, solid carcinomaes, because the tissue factor of expressing on tumor cell contacts with blood, blood coagulation system overactivity and cause DIC.
In addition, sometimes with the extension of infectious and the non-infectious systemic inflammatory response syndrome that irrespectively causes (the following SIRS that abbreviates as sometimes) by serious clinical invasion and attack in cause DIC.
SIRS is because the struvite cytokine that accompanies with serious tissue injury or severe infection disease produces hyperfunction caused condition of illness, if this overresponse carries out, then because the activation of neutrophilic granulocyte or the activation of vascular endothelial cell cause DIC.Promptly, SIRS is the preparatory stage (the following preDIC that abbreviates as sometimes) of DIC, DIC therapeutic agent of the present invention and/or improving agent also can use in preDIC effectively, also comprise treatment and/or the improvement of preDIC in the therapeutic agent of the DIC among the present invention and/or the improving agent.
The clinical symptoms of DIC is different and different according to the kind of basic disease, diagnostic method as DIC, except observing bleeding, internal organs symptom, preferably DIC is marked by several check the values as described below, be diagnosed as DIC when reaching certain necessarily above scoring.As check the value, for example can enumerate the platelet count in the blood, through the zymolytic fibrin of fibrinolytic and Fibrinogen catabolite (the following FDP that abbreviates as sometimes) concentration, D-bipolymer concentration, fibrinogen concentration or prothrombin time etc.In addition, can DIC not marked yet, by blood platelet reduction, D-dimer or the rising of FDP concentration wait diagnose preDIC (middle river refined husband 《 Bo Seed IC (and DIC) ?disconnected basic Quasi utilize に Seki す る Tone to look into Reported to accuse (the relevant investigation report that utilizes disseminated inravascular coagulation (DIC) diagnostic criteria) " the specific illness blood coagulation disorder of Health and human services department disease investigation class, put down into 11 Annual Research Report books, 1999:65-72; The outlet gram is " the early stage Zhi Treatment of DIC Open primordium Quasi に Seki The Ru Try case To つ い て (beginning the reagent of standard about relevant DIC early treatment) " the specific illness blood coagulation disorder of Health and human services department disease investigation class, put down into 11 Annual Research Report books, 1999:73-77; In river Ke, Tsuji start, " DIC ?Duan Now shape-ア Application ケ — ト Tone Cha Knot fruit Reported accuse (present situation of DIC diagnosis-questionnaire survey result report) " clinical blood, 1999,40:362-364).Further, also can diagnose preDIC by soluble fibrin concentration or the thrombin-antithrombase complex concentration measured in the blood.As diagnostic criteria to the DIC scoring, specifically, for example can enumerate, the diagnostic criteria of Overt DIC (Taylor FB et al., Thromb Haemost2001,86:1327-1330), acute stage DIC diagnostic criteria (Gando S et al., Clin ApplThromb Hemost 2005,11 (1): 71-76) or the DIC diagnostic criteria of Health and human services department (blue or green wood prolongs hero, the Chang Gu river is pure, and DIC ?breaks, and " inspection that the disconnected め Fill of ?helps becomes basic Quasi
,
See " Entries changes Order To つ い て (about the revision of " diagnostic auxiliary examination achievement, the observed result " of DIC diagnostic criteria one), and the specific illness blood coagulation disorder of Health and human services department disease investigation class puts down into 4 Annual Research Report books, 1988:p37-41).
As the diagnostic method of DIC,, be preferably diagnostic method to the DIC scoring if above-mentioned diagnostic method does not then limit especially.In addition, consider, be necessary DIC also to have the alternate manner of preferred preDIC diagnosis when treating in early days from therapeutic effect, medical care expenses or patient's QOL (quality of life) aspect.
As diagnostic method, except above-mentioned diagnostic method, also can be the diagnostic method of similarly DIC being marked to the DIC scoring.
The application of DIC therapeutic agent of the present invention and/or improving agent is not subjected to the qualification of DIC kind, but more preferably at the DIC that comes from the hemopoietic system malignant tumor or come among the DIC that infects disease and use, further preferably uses in coming from the DIC that infects disease.As the object lesson that comes from the DIC that infects disease, can enumerate the preferred example of DIC conduct that comes from septicemia.As preferred alternate manner, also can enumerate the application in the DIC that comes from the hemopoietic system malignant tumor in addition.
Therapeutic agent of the present invention and/or improving agent also can use at septicemia sometimes.Septicemia also is positioned as by infective serious caused SIRS of clinical invasion and attack, has confidential relation with the DIC that with infection disease is origin cause of formation disease.Frequent concurrent DIC in the septicemia also can use medicine of the present invention to the septic patient of this DIC of being accompanied with sometimes.That is, among the present invention, sometimes can be to suffering from or suspecting that the patient who suffers from any one or two kinds in DIC or the septicemia uses.
Known septicemia is following severe systemic infection disease: to infect diseases such as disease, malignant tumor, liver cirrhosis, renal failure, diabetes, abnormal labor; Or the treatment that inlying catheter, infusion set, dialysis, tracheotomy etc. carry out at wound or disease is cause, and microorganism constantly or intermittently invades the blood from focus of infection.If severity of symptoms, then bring out septic shock, promptly because the shock that rapid blood pressure reduces, general is brought out in the depletion of tip circulatory function, thereby because the obstacle of important organs such as lung, kidney, liver, heart, digestive tract and central nervous system causes death.In addition, as the complication of following septicemia, can bring out DIC, or owing to the activation of neutrophilic granulocyte and to the migration accumulation pulmonary capillary obstacle together of pulmonary parenchyma bring out edema with interstitial lung, hemorrhage or acute respiratory failure is the adult respiratory distress syndrome (ARDS) of feature, the prognosis non-constant that becomes.
There is several method in diagnostic method as septicemia.This is at Levy M.et al., and Crit.Care.Med. sums up among the 31:1250-1256.For example comprise by the doctor and carry out the method for this diagnosis or use the method for check the value etc.As the latter's example, comprise following method: 1) body temperature 38 ℃ or＜36 ℃; 2) heart rate〉90/ minute; 3) respiratory frequency〉20/ minute or be necessary to practice artificial respiration; 4) leukocyte count〉12000/mm
3Or＜4000/mm
3, or blastocyte 10%; In these 4, be diagnosed as SIRS when satisfying 2, be proved to be for or doubtful for being that the SIRS of the cause of disease is diagnosed as septicemia [LaRosa S., the homepage of The Cleveland Clinic] with the microorganism.Proximate therewith method is at Members of the American College of Chest Physicians/Society of CriticalCare Medicine Consensus Conference:Crit Care Med, 20, on the books among the 864-874 (1992).
As the state of septic patient, for example can enumerate bacteremia, septicemia (septicemia), systemic inflammatory response syndrome (SIRS), septicemia (be proved to be for or doubtful for being the SIRS of the cause of disease), serious symptom septicemia, septic shock, intractable septic shock or multiple organs dysfunction (below be sometimes referred to as MODS) (the 15th edition 124 P828-833Medical Sciences International of the inferior internal medicine original work of Harry) with the microorganism.Can enumerate above-mentioned each state as therapeutic agent of the present invention and/or the effective symptom of improving agent.
As bacteremia, can enumerate the state that has antibacterial in the blood that confirms, the existence of this antibacterial proves by the blood cultivation positive.
As septicemia (septicemia), can enumerate the state that has microorganism or other toxin in the blood that confirms.
As systemic inflammatory response syndrome (SIRS), can enumerate the state that is in the DIC preparatory stage as mentioned above.
As the serious symptom septicemia, can enumerate one or more the septicemia in the depleted or hypotensive symptom such as the organ function that is attended by metabolic acidosis, acute encephalopathy, oliguria, hypoxemia or disseminated inravascular coagulation.
As septic shock, can enumerate reactionless under the hypotension (blood pressure is below the 90mmHg or below the blood pressure than the low 40mmHg of common blood pressure), as to be attended by organ function depletion septic shock to the recovery method of being undertaken by fluid infusion.
As intractable septic shock, can enumerate septic shock and continue more than 1 hour, the unresponsive intractable septic shock of fluid infusion pressor agent.
As multiple organs dysfunction (MODS), can enumerate the nonfunction, the multiple organs dysfunction that there are 1 above internal organs in order to keep homeostasis to need medical science to get involved.
DIC therapeutic agent of the present invention and/or improving agent can be used for AT effectively and reduce the patient.The AT activity value that AT reduction patient refers in the blood plasma is the patient who compares the state that is in the reduction of AT activity value below 70%, with the normal person.Reduce the patient as AT, can enumerate congenital AT and lack patient or posteriority AT shortage patient.Congenital AT lacks the patient and refers to born AT activity value and be lower than the normal person, be about 35～75% patient, and posteriority AT lacks the patient and refers to the AT activity value and be reduced to patient below 70% day after tomorrow.Reason as the reduction day after tomorrow of AT activity value, specifically, can enumerate the medicine reduction of digestive tract disease such as nephropathy, inflammatory bowel, heparin etc. such as hepatopathy, postoperative, shock, severe infection disease, nephrotic syndrome such as chronic liver failure, because the reduction that causes at advanced age, neonate, diabetes, Behcet disease or the malnutrition of premature labor.Among the present invention AT being reduced the patient is qualification especially geneogenous or posteriority, gets final product so long as AT reduces the patient.Ethnic group to the patient does not limit especially, but is preferably the Japanese.
Wherein, by DIC therapeutic agent and/or the improving agent that contains thrombomodulin as effective ingredient of the present invention, can treat and/or improve AT activity value in the blood plasma effectively less than the symptom of 50% patient's DIC.
During the AT activity is defined as and the activity of the blood coagulation activity of thrombin or the active form X factor, as common example, the AT activity value can be enumerated to represent with respect to the active relative value of AT who obtains by the blood plasma (hereinafter referred to as normal plasma) that is obtained by health adult.The normal plasma that uses is not particularly limited, so long as the normally used normal plasma of those skilled in the art gets final product, can use the biologic criteria Committee of Experts (ExpertCommittee on Biological Standardization (the following ECBS that abbreviates as sometimes)) to establish by The World Health Organization (WHO), Britain's country's biologic criteria and control institute (National Institute for Biological Standards andControl (the following NIBSC that abbreviates as sometimes)) management, the international standard substance (NIBSC system) of the normal plasma that distributes.Also can enumerate to use and proofread and correct the active commercially available standard blood plasma of AT with the international standard substance of NIBSC (for example can enumerate, the science of international thrombosis and hemostasis association and standardization committee (the standard blood plasma of Scientific and Standardization Committee (the following SSC that abbreviates as sometimes), International Society on Thrombosis and Haemostasis (the following ISTH that abbreviates as sometimes)) are as preferred example.Further, also can use normal plasma or the specified normal plasma of AT activity value mensuration test kit of measuring apposition in the test kit at common AT activity value.Measure the specified normal plasma of test kit as normal plasma or the AT activity value of measuring apposition in the test kit at common AT activity value, can enumerate normal plasma agent " first " (first chemical drugs) as preferred example.Use the AT activity value of the plasma sample that normal plasma measures preferably to be scaled sometimes with the normal plasma of the international standard substance of NIBSC AT activity value as benchmark.More preferably being scaled with normal plasma agent " first " (first chemical drugs) is that the AT activity value of benchmark is tried to achieve the AT activity value.
Preferably use the international standard substance of NIBSC as normal plasma.In addition, also there is the preferred alternate manner of having proofreaied and correct the active commercially available standard blood plasma of AT with the international standard substance of NIBSC that uses.As the preferred mode of normal plasma, can enumerate normal plasma agent " first " (first chemical drugs).For example, the AT activity value in the blood plasma is that to refer to the AT activity be 50% with respect to the ratio of above-mentioned normal plasma for 50% situation.
In order to treat and/or improve the symptom of DIC effectively, AT activity value in DIC patient's the blood plasma is not particularly limited, as long as less than 50%, the upper limit is preferably below 48%, more preferably below 46%, more preferably below 44%, be preferably below 42% especially, most preferably be below 40%, lower limit is not particularly limited, as long as more than the detection limit for the said determination method, can enumerate more than 0.1%, be preferably more than 10%, more preferably more than 15%, more preferably more than 20%, be preferably more than 25% especially, the AT activity value of patient's group of the test example 1 from embodiment is considered, most preferably is more than 30%.
In addition, according to the present invention, a kind of therapeutic agent and/or improving agent of disseminated intravascular coagulation are provided, and it is to be the medicine of effective ingredient with the thrombomodulin, and this medicine is used for being applied to the disseminated intravascular coagulation patient after the antithrombin activity value of measuring blood plasma.Therapeutic agent of the present invention and/or improving agent are not particularly limited, get final product so long as be applied to disseminated intravascular coagulation patient's medicine after the antithrombin activity value in measuring blood plasma, but preferably be used at the therapeutic agent and/or the improving agent of the antithrombin activity value of measuring less than the disseminated intravascular coagulation that was applied to the disseminated intravascular coagulation patient at 50% o'clock.So after the antithrombin activity value in measuring blood plasma thrombomodulin is applied to the disseminated intravascular coagulation patient, give full play to drug effect aspect be preferred.
In addition, DIC therapeutic agent of the present invention and/or improving agent also can be to being attended by because the patient that the AT that hepatopathy, postoperative, shock, severe infection diseases etc. such as chronic liver failure cause reduces application.
Thrombomodulin among known the present invention has that (1) optionally combines with thrombin, (2) promote the activatory effect based on the PROTEIN C of thrombin.Preferably also confirming (3) usually prolongs based on the effect of the clotting time of thrombin and/or (4) and suppresses effect based on the platelet aggregation of thrombin.Sometimes the effect that these thrombomodulins are had is called the thrombomodulin activity.
As the thrombomodulin activity, preferably have the effect of above-mentioned (1) and (2), further preferably have whole effects of above-mentioned (1)～(4).
For the activatory effect that promotes based on the PROTEIN C of thrombin, for example can by with Japanese kokai publication sho 64-6219 communique be in the various known document of representative clearly the test method of record easily confirm to promote the live vol of activatory effect of PROTEIN C or its to have or not.In addition, can easily confirm too based on the effect of the platelet aggregation of thrombin based on the effect and/or the inhibition of the clotting time of thrombin for prolongation.
Thrombomodulin among the present invention is not particularly limited,, is preferably soluble thrombomodulin as long as have the thrombomodulin activity.Deliquescent preferred example as soluble thrombomodulin, can enumerate for water, for example distilled water for injection (under the situation that does not have surfactants such as triton x-100 or polidocanol, usually near neutrality) be more than the 1mg/mL or for more than the 10mg/mL, it is above or for more than the 17mg/mL to be preferably 15mg/mL, more preferably 20mg/mL is above, 25mg/mL above or more than the 30mg/mL, be preferably especially more than the 60mg/mL, can enumerate respectively in some cases more than the 80mg/mL or more than the 100mg/mL.Judge when whether soluble thrombomodulin is dissolved, after the dissolving, under for example white light source, the position perusal of about 1000 lux brightness, will clarification this moment, do not contain and can know that the insoluble substance that confirms is interpreted as tangible index.In addition, also can filter affirmation and have or not residue.
As the thrombomodulin among the present invention, preferably be contained in the human thrombomodulin the 19th～132 aminoacid sequence as the active centre of thrombomodulin known sequences number 1, as long as comprise the 19th～132 aminoacid sequence of serial number 1, then do not limit especially.As long as the 19th～132 aminoacid sequence of this serial number 1 have promotion based on the activatory effect of the PROTEIN C of thrombin, be the thrombomodulin activity, nature or artificial variation then also can take place, and promptly can replace, lack, be added with one or more aminoacid in the 19th～132 aminoacid sequence of serial number 1.The degree of variation of allowing is not particularly limited, as long as it is active to have thrombomodulin, for example as aminoacid sequence, can enumerate homogeny more than 50%, be preferably homogeny more than 70%, more preferably the homogeny more than 80%, more preferably the homogeny more than 90%, especially be preferably homogeny more than 95%, most preferably be the homogeny more than 98%.This aminoacid sequence is called identical series of variation.For this variation, as described below, can use common gene manipulation techniques easily to obtain.
The sequence of serial number 3 is that the 125th aminoacid Val variation of the sequence of serial number 1 is the sequence behind the Ala, as the thrombomodulin among the present invention, also preferably comprises the 19th～132 aminoacid sequence of serial number 3.
So, thrombomodulin among the present invention is not particularly limited, as long as comprise the 19th～132 sequence of serial number 1 or serial number 3, or have the identical series of variation of above-mentioned sequence at least and have the active peptide sequence of thrombomodulin at least and get final product, as preference, can enumerate the peptide that the sequence by serial number 1 or serial number 3 in separately the 19th～132 or the 17th～132 forms, or has the active peptide of thrombomodulin at least by what the identical series of variation of above-mentioned sequence formed, the more preferably peptide that forms by the 19th～132 sequence of serial number 1 or serial number 3.In addition, the alternate manner that has the active peptide of thrombomodulin at least that also exists more preferably the identical series of variation by serial number 1 or serial number 3 in separately the 19th～132 or the 17th～132 to form.
In addition,, preferably comprise the 19th～480 aminoacid sequence of serial number 5, then do not limit especially as long as comprise the 19th～480 aminoacid sequence of serial number 5 as the alternate manner of the thrombomodulin among the present invention.The 19th～480 aminoacid sequence of this serial number 5 also can be its identical series of variation, if having promotion based on the activatory effect of the PROTEIN C of thrombin, be that thrombomodulin is active.
The sequence of serial number 7 is that the 473rd aminoacid Val variation of the sequence of serial number 5 is the sequence behind the Ala, as the thrombomodulin among the present invention, also preferably comprises the 19th～480 aminoacid sequence of serial number 7.
So, thrombomodulin among the present invention is not particularly limited, as long as comprise the 19th～480 sequence of serial number 5 or serial number 7, or have the identical series of variation of above-mentioned sequence at least and have the active peptide sequence of thrombomodulin at least and get final product, as preference, can enumerate the peptide that the sequence by serial number 5 or serial number 7 in separately the 19th～480 or the 17th～480 forms, or has the active peptide of thrombomodulin at least by what the identical series of variation of above-mentioned sequence formed, the more preferably peptide that forms by the 19th～480 sequence of serial number 5 or serial number 7.In addition, the alternate manner that has the active peptide of thrombomodulin at least that also exists more preferably the identical series of variation by serial number 5 or serial number 7 in separately the 19th～480 or the 17th～480 to form.
In addition,, preferably comprise the 19th～515 aminoacid sequence of serial number 9, then do not limit especially as long as comprise the 19th～515 aminoacid sequence of serial number 9 as the alternate manner of the thrombomodulin among the present invention.The 19th～515 aminoacid sequence of this serial number 9 also can be its identical series of variation, if having promotion based on the activatory effect of the PROTEIN C of thrombin, be that thrombomodulin is active.
The sequence of serial number 11 is that the 473rd aminoacid Val variation of the sequence of serial number 9 is the sequence behind the Ala, as the thrombomodulin among the present invention, also preferably comprises the 19th～515 aminoacid sequence of serial number 11.
So, thrombomodulin among the present invention is not particularly limited, as long as comprise the 19th～515 sequence of serial number 9 or serial number 11, or have the identical series of variation of above-mentioned sequence at least and have the active peptide sequence of thrombomodulin at least and get final product, as preference, can enumerate by in separately the 19th～516 of serial number 9 or serial number 11, the 19th～515, the peptide that the 17th～516 or the 17th～515 's sequence forms, or have the active peptide of thrombomodulin at least by what the identical series of variation of above-mentioned sequence formed, preferred especially by the 19th～516 in the serial number 9, the 19th～515, the peptide that the 17th～516 or the 17th～515 's sequence forms.The mixture that can also enumerate them is as preferred example.In addition, the alternate manner that also has especially preferably the peptide that the sequence by the 19th～516 in the serial number 11, the 19th～515, the 17th～516 or the 17th～515 forms.The mixture that can also enumerate them is as preferred example.That further, can also enumerate that identical series of variation by above-mentioned sequence forms has the active peptide of thrombomodulin at least as preferred example.
As mentioned above, the peptide with identical series of variation refers to and can replace, lack, be added with in the aminoacid sequence of the peptide that becomes object more than one (one or more, further preferably a plurality of (for example 1～20, be preferably 1～10, more preferably 1～5, be preferably 1～3 especially)) amino acid whose peptide.The degree of variation of allowing is not particularly limited, as long as it is active to have thrombomodulin, for example as aminoacid sequence, can enumerate homogeny more than 50%, be preferably homogeny more than 70%, more preferably the homogeny more than 80%, more preferably the homogeny more than 90%, especially be preferably homogeny more than 95%, most preferably be the homogeny more than 98%.
Further, as thrombomodulin of the present invention, peptide that can also enumerate peptide that the sequence by serial number 14 (462 amino acid residues) among the Japanese kokai publication sho 64-6219 forms, is formed by the sequence (272 amino acid residues) of serial number 8 or the peptide that formed by the sequence (236 amino acid residues) of serial number 6 are as preferred example.
Thrombomodulin among the present invention is not particularly limited, get final product so long as have the peptide of the 19th～132 aminoacid sequence of serial number 1 or serial number 3 at least, the peptide that wherein preferably has the 19th～480 aminoacid sequence of serial number 5 or serial number 7 at least more preferably has the peptide of the 19th～515 aminoacid sequence of serial number 9 or serial number 11 at least.As the peptide of the 19th～515 the aminoacid sequence that has serial number 9 or serial number 11 at least, can enumerate peptide that the sequence by serial number 9 or serial number 11 in separately the 19th～516, the 19th～515, the 17th～516 or the 17th～515 forms as preferred example.In addition, can also enumerate peptide that the sequence by serial number 9 or serial number 11 in separately the 19th～516, the 19th～515, the 17th～516 or the 17th～515 forms at serial number 9 or serial number 1l mixture separately as preferred example.
In the situation of said mixture, as by serial number 9 or serial number 11 in separately since the 17th peptide and mixed proportion since the 19th peptide, can enumerate (30:70)～(50:50), be preferably (35:65)～(45:55).
In addition, as serial number 9 or serial number 11 in separately to the peptide of the 515th end and mixed proportion to the peptide of the 516th end, can enumerate (70:30)～(90:10), be preferably (75:25)～(85:15).
The mixed proportion of these peptides can be tried to achieve by usual method.
Need to prove that the 19th～132 sequence of serial number 1 is equivalent to the 367th～480 sequence of serial number 9, the 19th～480 sequence of serial number 5 is equivalent to the 19th～480 sequence of serial number 9.
In addition, the 19th～132 sequence of serial number 3 is equivalent to the 367th～480 sequence of serial number 11, and the 19th～480 sequence of serial number 7 is equivalent to the 19th～480 sequence of serial number 11.
Further, serial number 1,3,5,7,9 all is identical sequence with 11 the 1st～18 sequences in separately.
As described later, these thrombomodulins of the present invention can be from DNA (specifically, being respectively base sequences such as serial number 2, serial number 4, serial number 6, serial number 8, serial number 10 or the serial number 12) transfection of the peptides such as these serial numbers 1,3,5,7,9 or 11 of will encoding by carrier to host cell in prepared transformant obtain.
Further, these peptides can add sugar chain or not additional sugar chain if having above-mentioned aminoacid sequence gets final product, and this point is not limited especially.In addition, in genetic manipulation, according to the variety classes of the host cell that uses, the kind of sugar chain, additional position or additional degree difference can be used arbitrarily.For the binding site and the kind of sugar chain, the content of putting down in writing among the known Japanese kokai publication hei 11-341990 also can be added identical sugar chain for the thrombomodulin among the present invention on identical position.As described later, be not limited to obtain by genetic manipulation, but when obtaining by genetic manipulation, as the signal sequence that can when expressing, use, can utilize the base sequence, other common known signal sequence (for example signal sequence of human histiotype plasminogen activator (international No. 88/9811 communique, the Japanese kokai publication hei 11-341990 of disclosing)) of the 1st～16 aminoacid sequence of the base sequence, coded sequence numbers 9 of the 1st～18 aminoacid sequence of the above-mentioned serial number 9 of coding.
With the DNA sequence of coding thrombomodulin when importing in the host cell, the method that imports in the DNA sequence of the thrombomodulin of preferably will the encode introducing carrier (the especially preferably expression vector that can in zooblast, express).Expression vector refers to by promoter sequence, mRNA is given the sequence of ribosome binding site, be used to encode and desire the DNA sequence of expressed proteins, splicing signal, transcribe the terminator sequence of end, the dna molecular that replication initiation sequence etc. constitute, example as the preferred animal fibrocyte expression vector, can enumerate the pSV2-X of people [Proc.Natl.Acad.Sci.U.S.A.78.2072 (1981)] such as R.C.Mulligan report, or people [Methods in Emzymology such as P.M.Howleys, 101,387, Academic Press (1983)] pBP69T (69-6) etc. of report.
As the host cell that can when preparing these peptides, use, can enumerate Chinese hamster ovary (CHO) cell, COS-1 cell, COS-7 cell, VERO (ATCC CCL-81) cell, bhk cell, the mdck cell that comes from Testis et Pentis Canis, hamster AV-12-664 cell etc., as human archeocyte, can enumerate HeLa cell, W138 cell, people's 293 cells in addition.Usually Chinese hamster ovary celI very preferably, in Chinese hamster ovary celI, further preferred DHFR-CHO cell.
In addition, in the preparation process of the process of genetic manipulation or peptide, use microorganisms such as escherichia coli, the preferred host-vector system that is fit to separately that uses also can be selected the appropriate carriers system in above-mentioned host cell also morely.The gene of the thrombomodulin that uses in gene recombination technology is through the clone, and the Production Example of utilizing the thrombomodulin of gene recombination technology has obtained open, also become known for obtaining the purification process [Japanese kokai publication sho 64-6219 communique, Japanese kokai publication hei 2-255699 communique, Japanese kokai publication hei 5-213998 communique, Japanese kokai publication hei 5-310787 communique, Japanese kokai publication hei 7-155176 communique, J.Biol.Chem., 264:10351-10353 (1989)] of purification product in addition.Therefore, the thrombomodulin that uses among the present invention can be by using the method put down in writing in the above-mentioned report or preparing according to the method for wherein record.For example, in Japanese kokai publication sho 64-6219 communique, the Escherichia coli K-12strain DH5 (No. 67283, ATCC deposit number) of the plasmid pSV2TMJ2 of the DNA that contains the thrombomodulin that comprises the total length that is used to encode is disclosed.In addition, can also use the bacterial strain (Escherichia coliDH5/pSV2TMJ2) (FERM BP-5570) that this bacterial strain is ground (existing Independent Administrative Leged Industrial Technology Complex Inst speciallys permit biological preservation center) preservation again at life.Can by known gene manipulation techniques, prepare thrombomodulin of the present invention with the DNA of the thrombomodulin of this total length that is used to encode as raw material.
The thrombomodulin that uses among the present invention prepares with existing known method or according to existing known method and gets final product, for example can be with reference to people's such as above-mentioned Yamamoto method [Japanese kokai publication sho 64-6219 communique] or Japanese kokai publication hei 5-213998 communique.That is, the thrombomodulin gene in people source is made the DNA of aminoacid sequence of coded sequence for example numbers 9 by gene manipulation techniques after, also can further change as required.As this change, for example for the DNA (base sequence of serial number 12 specifically) of the aminoacid sequence of making coded sequence numbers 11, the 473rd amino acid whose codon (particularly the 1418th base) to the aminoacid sequence of coded sequence numbers 9 utilizes Method in Enzymology, 100:468 (nineteen eighty-three), the method for putting down in writing among the Academic Press is carried out the locus specificity variation.For example, can use variation to form the DNA that the 1418th base T of serial number 10 is converted into base C with synthetic DNA with the base sequence shown in the serial number 13.
For example the DNA that so prepares can be imported in Chinese hamster ovary (CHO) cell, make transformant, suitably select, utilize known method by the thrombomodulin of cultivating the inoculum preparation purification that this cell obtains.As mentioned above, preferably with DNA (serial number 10) transfection of the aminoacid sequence of coded sequence numbers 9 in above-mentioned host cell.The production method of the thrombomodulin that uses among the present invention is not limited to said method, for example also can be from urine, blood or other body fluid etc. abstraction purification, or from the tissue of producing thrombomodulin or these tissue culture mediums etc. abstraction purification, or further cut off processing as required by protease.
When preparing thrombomodulin among the present invention,, can find that N-terminal aminoacid has multiformity sometimes by proteinic post translational modification by above-mentioned cell culture processes.For example, the 17th, 18,19 in the serial number 9 or 22 aminoacid can form N-terminal sometimes.In addition, for example be changed to pyroglutamic acid as the 22nd glutamic acid rotating, N-terminal aminoacid can be modified sometimes.Preferred the 17th or 19 s' aminoacid forms N-terminal, and more preferably the 19th aminoacid forms N-terminal.In addition, also exist preferred the 17th aminoacid to form the alternate manner of N-terminal.Above-mentioned modification or multiformity etc. also can be enumerated same example for serial number 11.
Further, when using the DNA of base sequence to prepare thrombomodulin, find the amino acid whose multiformity of C-terminal sometimes, prepare the peptide of few 1 amino acid residue sometimes with serial number 10.That is, form C-terminal as the 515th aminoacid, and the 515th such by amidated situation, C-terminal aminoacid can be modified sometimes.Therefore, might prepare N-terminal aminoacid and C-terminal aminoacid and be rich in multifarious peptide or their mixture.Preferred the 515th aminoacid forms C-terminal.In addition, also exist preferred the 516th aminoacid to form the alternate manner of C-terminal.Above modification or multiformity etc. also are identical for the DNA of the base sequence with serial number 12.
The thrombomodulin that obtains by said method might be the mixture that N-terminal and C-terminal show multifarious peptide.Specifically, can enumerate the mixture of the peptide that the sequence by the 19th～516, the 19th～515, the 17th～516 of serial number 9 or the 17th～515 forms.
Then, for the method for separation and purification thrombomodulin from culture supernatant by above-mentioned acquisition or culture, can carry out according to known method [hole tail force one is compiled, the infrastest method of protein-enzyme].For example, preferred use to be fixed with have and the chromosorb of the functional group of thrombomodulin opposite charges and utilize interactional ion exchange chromatography or adsorption chromatography between thrombomodulin.In addition, can also enumerate the preferred example of affinity chromatography conduct of the specificity affinity of utilization and thrombomodulin.As the preferred example of adsorbate, can enumerate the example that the part that utilizes thrombomodulin is the antibody of thrombin or thrombomodulin.As this antibody, the antibody that has suitable character or discern the thrombomodulin of suitable epi-position can be utilized, the example of record in for example Japanese special fair 5-42920 communique, Japanese kokai publication sho 64-45398 communique, the Japanese kokai publication hei 6-205692 communique etc. can be enumerated.In addition, can enumerate the gel filtration chromatography or the ultrafiltration of the molecular weight size of utilizing thrombomodulin.And, can also enumerate the hydrophobicity chromatograph of the hydrophobic bonding between the hydrophobicity position that the chromosorb that is fixed with hydrophobic group and utilization and thrombomodulin had.In addition, can also use hydroxyapatite as carrier, can enumerate the example of putting down in writing in the Japanese kokai publication hei 9-110900 communique for example as adsorption chromatography.These methods can appropriate combination.The degree of purification can be according to selections such as application targets, for example is purified to preferably that the result of electrophoresis (preferred SDS-PAGE) obtains single band, or the result of the gel filtration HPLC of isolated purification product or reversed-phase HPLC forms single peak.Certainly, when using two or more thrombomodulin, preferably in fact only form the band of thrombomodulin, do not require to form single band.
If enumerate the method for purification among the present invention particularly, can enumerate with the thrombomodulin activity is the method that index is carried out purification, for example can enumerate following method: the Q-agarose Fast Flow by ion exchange column carries out thick purification to culture supernatant or culture, recovery has the active fraction of thrombomodulin, then utilize DIP-thrombin-agarose (diisopropylphosphorylthrombin agarose) chromatographic column of affinity chromatographic column to carry out main purification, reclaim the active strong fraction of thrombomodulin, concentrate and reclaim fraction, through form acquisition thrombomodulin active fractions [the Gomi K.et al. of gel filtration with pure product, Blood, 75:1396-1399 (1990)].For thrombomodulin activity, can enumerate for example active based on the activatory promotion of the PROTEIN C of thrombin as index.In addition, followingly enumerate preferred method of purification.
Ion-exchange chromatogram purification is carried out in selection and the suitable ion exchange resin that thrombomodulin has the good adsorption condition.More preferred example is to use the method for the Q-agarose Fast Flow that crosses through 0.02M Tris hydrochloride buffer (pH7.4) balance that contains 0.18M NaCl.Suitably after the washing, for example can obtain the thrombomodulin of thick purification product with 0.02M Tris hydrochloride buffer (pH7.4) eluting that contains 0.3M NaCl.
Then, for example the material that has a specificity affinity with thrombomodulin can be fixed on and carry out the affinity chromatography purification on the resin.As preferred example, can enumerate the example and the antithrombotic of DIP-thrombin-sepharose chromatography column and regulate the example of protein monoclonal antibody chromatographic column.DIP-thrombin-sepharose chromatography column is in advance with 20mM Tris hydrochloride buffer (pH7.4) balance that for example contains 100mM NaCl and 0.5mM calcium chloride, fill above-mentioned thick purification product, carry out suitable washing, with 20mM Tris hydrochloride buffer (pH7.4) eluting that for example contains 1.0M NaCl and 0.5mM calcium chloride, thereby can obtain the thrombomodulin of purification product.In addition, regulate in the protein monoclonal antibody chromatographic column, can enumerate following method: make to be dissolved with the 0.1M NaHCO that contains 0.5M NaCl that antithrombotic is regulated protein monoclonal antibody at antithrombotic
3Buffer (pH8.3) with contact by the activatory agarose 4FF of CNBr (GE Healthcare Bio-Sciences company) in advance, be filled with the chromatographic column of agarose 4FF and the link coupled resin of antithrombotic adjusting protein monoclonal antibody in advance with 20M phosphate buffer (pH7.3) balance that for example contains 0.3M NaCl, suitably after the washing, with 100mM glycinate acid buffer (pH3.0) eluting that for example contains 0.3M NaCl.Eluent also can obtain the purification product with suitable buffer neutralization.
After then the purification product that obtain being adjusted to pH3.5, be filled in the cation exchange column of crossing with 100mM glycinate acid buffer (pH3.5) balance that contains 0.3M NaCl (preferred strong cation exchange body SP-agarose FF (GE Healthcare Bio-Sciences company)), obtain non-adsorbed fraction with same buffer washing.The fraction that obtains can obtain high-purity purification product with suitable buffer neutralization.They preferably concentrate by ultrafiltration.
Further, preferably carry out buffer-exchanged by gel filtration.For example, can contain the high-purity purification product of filling in Sephacryl S-300 chromatographic column that 20mM phosphate buffer (pH7.3) balance of 50mM NaCl crosses or the S-200 chromatographic column to usefulness by ultrafiltration and concentration, launch to separate with the 20mM phosphate buffer (pH7.3) that contains 50mM NaCl, affirmation is active based on the activatory promotion of the PROTEIN C of thrombin, reclaim active fractions, thereby obtain high-purity purification product through buffer-exchanged.Safety preferably uses suitable virus to remove striping to the high-purity purification product that so obtain, for example Planova 15N (Asahi Medical Co) filters in order to improve, then can be by ultrafiltration and concentration to purpose concentration.Preferably filter by aseptic filter membrane at last.
The thrombomodulin that so obtains can be made freeze-dried preparation by usual way.That is, can enumerate following method: the solution of the additive that contains thrombomodulin and add as required is freezing, and the water that under reduced pressure distils carries out drying thus.
In the present invention, the AT activity value in the blood plasma can or be derived from AT activity value in the venous blood plasma for the AT activity value in the blood plasma that is derived from tremulous pulse, is preferably the AT activity value that is derived from the venous blood plasma.The situation that the AT activity value of preferred source in the blood plasma of tremulous pulse also arranged in addition.Be commonly referred to as the AT activity value that is derived from the venous blood plasma.Assay method to the AT activity value does not limit especially, for example can measure the AT activity value by the color rendering properties synthetic substrate method of being tried to achieve the AT activity value by active form factor X residual quantity.
Specifically, blood sample is collected in the blood taking tube that is added with sodium citrate, promptly carry out centrifugalize, reclaim blood plasma.Then in this blood plasma, add heparin and form AT-heparin complex, further, in this AT-heparin complex, add constant excessive active form factor X.The compound scale of construction of the AT-heparin of active form factor X in per sample forms AT-heparin-active form factor X complex, thus inactivation.After this complex forms reaction, add substrate liquid, react, free paranitroanilinum is carried out colorimetric assay, can measure residual active form factor X activity thus.Because the AT activity in this residual active form factor X active reaction sample can be tried to achieve the AT activity value by the standard curve of making in addition.The colorimetric assay of paranitroanilinum can use automatic analysing apparatus BM1650 (Jeol Ltd.'s system).In addition, standard curve can be made by using standard substance.
It is of the present invention that to contain thrombomodulin different and different according to the degree of patient's age, body weight, disease, route of administration etc. as 1 day dosage of the DIC therapeutic agent of effective ingredient and/or improving agent, common amount in thrombomodulin, the upper limit be preferably 5mg/kg following, more preferably 2mg/kg following, more preferably 1mg/kg following, be preferably below the 0.8mg/kg especially, lower limit be preferably 0.005mg/kg above, more preferably 0.01mg/kg above, more preferably 0.02mg/kg above, be preferably more than the 0.05mg/kg especially.
Administration in per 1 day 1 time or administration is several times as required.For dosing interval, can administration every day, also can administration in 2 days～14 days administration in 1 time, more preferably 3 days～10 days 1 time, further administration in preferred 4 days～7 days 1 time.
Particularly in intravenous administration, administration was 1 time in preferred per 1 day, but was not limited thereto.In addition, in subcutaneous administration, administration in preferred per 1 day 1 time or 1 all administrations 1 time can be adjusted dosing interval according to dosage.
As the thrombomodulin that contains of the present invention as the DIC therapeutic agent of effective ingredient and/or the medication of improving agent, can be by normally used medication, be non-oral administration method (for example, intravenous administration, intramuscular administration or subcutaneous administration etc.) administration.From prolonging the aspect consideration of dosing interval, preferred especially intramuscular administration or subcutaneous administration by long term maintenance blood drug level.In addition, the alternate manner that also has preferred intravenous administration.In addition, can also be oral administration, drop rectum with drug, intranasal administration, sublingual administration etc.
During intravenous administration, can enumerate disposable method or the instillation intravenous administration that gives required amount.
Consider the preferred disposable method that gives required amount from the aspect that administration time is short.During disposable administration, need the time usually with the syringe administration, required time of administration is different and different according to the amount of liquid of administration, but be generally below 2 minutes, more preferably below 1 minute, more preferably below 30 seconds.In addition, lower limit is not limited especially, be preferably more than 1 second, more preferably more than 5 seconds, more preferably more than 10 seconds.Dosage is not limited especially, so long as above-mentioned preferred dosage gets final product.
Keep constant aspect to consider from easy blood drug level with thrombomodulin, preferred instillation intravenous administration, so long as above-mentioned preferred dosage does not then limit especially, the upper limit as per 1 day dosage, be preferably 1mg/kg following, more preferably 0.5mg/kg following, more preferably 0.1mg/kg following, especially be preferably 0.08mg/kg following, most preferably be below the 0.06mg/kg, as lower limit, be preferably 0.005mg/kg above, more preferably 0.01mg/kg above, more preferably 0.02mg/kg above, be preferably more than the 0.04mg/kg especially.
Administration time during for the instillation intravenous administration, as the upper limit be preferably below 4 hours, more preferably below 3 hours, more preferably below 2 hours, be preferably below 1 hour especially, most preferably be below 30 minutes, as lower limit be preferably more than 10 minutes, more preferably more than 15 minutes, more preferably more than 20 minutes.
When being made for freeze-dried preparation, be applied to the patient after can utilizing dissolvings such as water, for example distilled water (or water for injection), normal saline during use.
In addition, preparation is during liquid preparation, can mix with the carrier that can be used for medicine by the thrombomodulin with effective dose to prepare.That is,, the thrombomodulin of effective dose can be mixed with the carrier of known appropriate amount, prepare the preparation that is suitable for being applied to effectively the patient in order to treat above-mentioned disease.For example, can add thickening agents such as sucrose, glycerol, methylcellulose, carboxymethyl cellulose; The pH regulator agent of various inorganic salts etc. prepares as additive.
[explanation of sequence table]
Serial number 1: the aminoacid sequence of coded by said gene that is used for the production of TME456
Serial number 2: the base sequence of the aminoacid sequence of coded sequence number 1
Serial number 3: the aminoacid sequence of coded by said gene that is used for the production of TME456M
Serial number 4: the base sequence of the aminoacid sequence of coded sequence numbers 3
Serial number 5: the aminoacid sequence of coded by said gene that is used for the production of TMD12
Serial number 6: the base sequence of the aminoacid sequence of coded sequence numbers 5
Serial number 7: the aminoacid sequence of coded by said gene that is used for the production of TMD12M
Serial number 8: the base sequence of the aminoacid sequence of coded sequence numbers 7
Serial number 9: the aminoacid sequence of coded by said gene that is used for the production of TMD123
Serial number 10: the base sequence of the aminoacid sequence of coded sequence numbers 9
Serial number 11: the aminoacid sequence of coded by said gene that is used for the production of TMD123M
Serial number 12: the base sequence of the aminoacid sequence of coded sequence numbers 11
Serial number 13: the variation synthetic DNA that uses when carrying out the locus specificity variation
Embodiment
Below, enumerate embodiment and the present invention is carried out specific description, but the present invention is not subjected to any qualification of these examples with the test example.
The thrombomodulin of the present invention that uses in the test example is that the method (method of record in Japanese kokai publication sho 64-6219 number) according to people such as above-mentioned Yamamotos prepares.Below this Production Example is described.
[Production Example 1]
The acquisition of＜thrombomodulin 〉
Obtain thrombomodulin by said method, promptly, with the DNA of the aminoacid sequence of coded sequence numbers 9 (specifically, be the base sequence of serial number 10) transfection in Chinese hamster ovary (CHO) cell, from the culture fluid of this transformant, obtain to have reclaimed the high-purity purification product of active fractions with the 20mM phosphate buffer (pH7.3) that contains 50mM NaCl with the method for purification of above-mentioned conventional method.Further carry out ultrafiltration, obtaining concentration is thrombomodulin (the following TMD123 that abbreviates as the sometimes) solution of 11.2mg/mL.
＜additive solution preparation 〉
In the rustless steel container made of 10L, measure adding 480g arginine hydrochloride (aginomoto society system), add 5L water for injection and dissolve.Add the 1M sodium hydroxide solution, pH is adjusted into 7.3.
＜medicinal liquid preparation-filling 〉
Above-mentioned additive solution full dose is joined in the rustless steel container made of 20L, add the above-mentioned TMD that obtains 123 solution of 2398mL (albumen quality in soluble thrombomodulin is equivalent to 26.88g, wherein excessive adding 12%), mix stirring.Further adding water for injection to total amount is 12L, mixes equably and stirs.This medicinal liquid is filter (Millipore the makes MCGL10S) filtration sterilization of 0.22 μ m with the aperture.Filtrate is filled into bottle (Vial), and every bottle of 1mL is with rubber stopper half tamponade.
＜lyophilization 〉
Order with lyophilization → filling nitrogen → rubber stopper total head plug → screw lid is carried out the lyophilization operation under the following conditions, and what obtain containing 2mg soluble thrombomodulin, 40mg arginine hydrochloride in 1 container contains the TMD123 preparation.
＜lyophilization condition 〉
Pre-cooled (with 15 minutes from room temperature to 15 ℃) → formal cooling (with 2 hours from 15 ℃ to-45 ℃) → keep (45 ℃ 2 hours) → vacuum (45 ℃ 18 hours) → heat up (with 20 hours from-45 ℃ to 25 ℃) → keep (25 ℃ 15 hours) → heat up (with 1 hour from 25 ℃ to 45 ℃) → maintenance (45 ℃ 5 hours) → room temperature (with 2 hours from 45 ℃ to 25 ℃) → press again nitrogen filling (extremely-100mgHg) → total head plug → screw lid
[Production Example 2]
With the DNA of the aminoacid sequence of coded sequence numbers 11 (specifically, being the base sequence of serial number 12) transfection is in Chinese hamster ovary (CHO) cell, method of purification with above-mentioned conventional method obtains purified thrombomodulin (the following TMD123M that abbreviates as sometimes) solution from the culture fluid of this transformant, obtain the freeze-dried preparation of TMD123M by method same as described above.
[Production Example 3]
With the DNA of the aminoacid sequence of coded sequence number 1 (specifically, being the base sequence of serial number 2) transfection is in Chinese hamster ovary (CHO) cell, method of purification with above-mentioned conventional method obtains purified thrombomodulin (the following TME456 that abbreviates as sometimes) from the culture fluid of this transformant, obtain the freeze-dried preparation of TME456 by method same as described above.
[Production Example 4]
With the DNA of the aminoacid sequence of coded sequence numbers 3 (specifically, being the base sequence of serial number 4) transfection is in Chinese hamster ovary (CHO) cell, method of purification with above-mentioned conventional method obtains purified thrombomodulin (the following TME456M that abbreviates as sometimes) from the culture fluid of this transformant, obtain the freeze-dried preparation of TME456M by method same as described above.
[Production Example 5]
With the DNA of the aminoacid sequence of coded sequence numbers 5 (specifically, being the base sequence of serial number 6) transfection is in Chinese hamster ovary (CHO) cell, method of purification with above-mentioned conventional method obtains purified thrombomodulin (the following TMD12 that abbreviates as sometimes) from the culture fluid of this transformant, obtain the freeze-dried preparation of TMD12 by method same as described above.
[Production Example 6]
With the DNA of the aminoacid sequence of coded sequence numbers 7 (specifically, being the base sequence of serial number 8) transfection is in Chinese hamster ovary (CHO) cell, method of purification with above-mentioned conventional method obtains purified thrombomodulin (the following TMD12M that abbreviates as sometimes) from the culture fluid of this transformant, obtain the freeze-dried preparation of TMD12M by method same as described above.
[test example 1]
For the DIC diagnostic criteria based on Health and human services department as follows be diagnosed as DIC because hemopoietic system malignant tumor or infect disease and the DIC patient of induced symptom, give DIC therapeutic agent of the present invention and/or improving agent, the 28th day patient's survival rate after the investigation beginning administration by following method preparation.
Need to prove, also do not use the AT preparation in during the administration of DIC therapeutic agent of the present invention and/or improving agent.
＜preparation example 1 〉
In the freeze-dried preparation of the TMD123 that obtains according to Production Example 1, add normal saline, the liquid to be checked of preparation 0.5mg/ml.
The mensuration of＜AT activity value 〉
The blood sample 4.5ml of the subject patient before the beginning administration day administration of DIC therapeutic agent of the present invention and/or improving agent is collected in the blood taking tube that is added with 0.5ml 3.8% sodium citrate, put upside down mixing, centrifugal after, reclaim blood plasma, freezing preservation.Then in this blood plasma, add heparin, form AT-heparin complex, further, in this AT-heparin complex, add excessive factor Xa.After this complex forms reaction, add substrate liquid (Test-team S ATIII (CHROMOGENIX corporate system)), react, free paranitroanilinum is measured absorbance under 410nm, carry out colorimetric assay, measure residual factor xa activity (Test-team S ATIII additional disclosure book) thus.Because the AT activity in this residual factor xa activity reflection sample uses the standard curve of making in addition to try to achieve the AT activity value.The colorimetric assay of paranitroanilinum uses automatic analysing apparatus BM1650 (Jeol Ltd.'s system).In addition, as the normal plasma that is used to try to achieve the AT activity value, use normal plasma agent " first " (first chemical drugs).
＜dosage and medication 〉
For the DIC subject patient, gather the liquid to be checked for preparing in the preparation example with the ratio of 0.12ml/kg (being equivalent to 0.06mg/kg), join in the normal saline, make 100ml.The intravenous drip in 30 minutes of this normal saline solution 1 usefulness every day.This operation repeats 6 days.
＜result 〉
Give liquid to be checked by above-mentioned medication, the 28th day death after the investigation beginning administration, the AT activity value is 50% or more and less than the survival rate of patient's group of 70% to be 64.3%, and the AT activity value is that the survival rate that the patient more than 70% organizes is 80%.On the other hand, for the survival rate of AT activity value less than 50% patient group, dead example is 1 example only, and survival rate is 92.3%, for above-mentioned 2 groups of survival rates that show advantage.Its result is as shown in table 1.
In addition, wherein the AT activity value is that survival rate is 100% among patient's (5 example) below 40%.
[table 1]
[test example 2]
By (body weight 180～240g) gives the Mus AT of rabbit Chinese People's Anti-Japanese Military and Political College antibody (20mg/kg) to the tail intravenous, makes that the AT activity value is reduced to less than 60% in the rat plasma to male Sprague-Dawley rat.Give antibody after 1 hour, under pentobarbital anesthesia, continued in rat tail vein, to give tissue factor with 1 hour and (be derived from the Thromboplastin of rabbit; 90mg/kg).The thrombomodulin of the various Production Examples among the present invention of 0.1～10mg/kg was administered to rapidly the tail intravenous of opposition side before being about to give tissue factor.Finish the back by the abdominal aortic blood sampling at tissue factor,, investigate the therapeutic effect of DIC and/or improve effect, can confirm effect of the present invention by measuring platelet count, Fibrinogen or AT activity value.
Industrial applicibility
The preparation that contains thrombomodulin of the application of the invention, can preferably not with AT Effectively treat under the condition that is used in combination and/or improve AT activity value in the blood plasma less than 50% DIC patient's symptom.
Sequence table
＜110〉Asahi Kasei Pharma Corp
＜120〉therapeutic agent of disseminated intravascular coagulation and/or improving agent
<130>F107098-WO
<160>13
<210>1
<211>132
<212>PRT
＜213〉people
<400>1
<210>2
<211>396
<212>DNA
＜213〉people
<400>2
<210>3
<211>132
<212>PRT
＜213〉people
<400>3
<210>4
<211>396
<212>DNA
＜213〉people
<400>4
<210>5
<211>480
<212>PRT
＜213〉people
<400>5
<210>6
<211>1440
<212>DNA
＜213〉people
<400>6
<210>7
<211>480
<212>PRT
＜213〉people
<400>7
<210>8
<211>1440
<212>DNA
＜213〉people
<400>8
<210>9
<211>516
<212>PRT
＜213〉people
<400>9
<210>10
<211>1548
<212>DNA
＜213〉people
<400>10
<210>11
<211>516
<212>PRT
＜213〉people
<400>11
<210>12
<211>1548
<212>DNA
＜213〉people
<400>12
<210>13
<211>21
<212>DNA
＜213〉artificial sequence
<220>
＜223〉artificial sequence note: synthetic DNA
<400>13
Claims (10)
1. the therapeutic agent of a disseminated intravascular coagulation and/or improving agent, it is to be the medicine of effective ingredient with the thrombomodulin, the antithrombin activity value that this medicine is used for being applied to blood plasma is less than 50% disseminated intravascular coagulation patient.
2. the therapeutic agent of disseminated intravascular coagulation as claimed in claim 1 and/or improving agent, wherein, described thrombomodulin is a soluble thrombomodulin.
3. the therapeutic agent of disseminated intravascular coagulation as claimed in claim 1 or 2 and/or improving agent, wherein, described thrombomodulin is the peptide that is obtained by transformant, and described transformant is to prepare in host cell by the DNA transfection with the aminoacid sequence of record in coded sequence numbers 9 or the serial number 11.
4. as the therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation of claim 1～3, wherein, described thrombomodulin is the peptide with serial number 9 or serial number 11 sequence of the 19th～516 in separately, or has in the aminoacid sequence of described peptide and replace, lack or added one or more amino acid whose aminoacid sequence and had the active peptide of thrombomodulin.
5. as the therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation of claim 1～4, wherein, the disseminated intravascular coagulation patient is that the antithrombin activity value in the blood plasma is the patient below 40%.
6. as the therapeutic agent and/or the improving agent of any described disseminated intravascular coagulation of claim 1～5, it is characterized in that, its not with the antithrombase combination medicine-feeding.
7. medicine, it is the medicine that is used to reduce the dead probability of the human patients of suffering from disseminated intravascular coagulation, wherein, this medicine is an effective ingredient with the thrombomodulin, is used for being applied to blood plasma antithrombin activity value less than 50% disseminated intravascular coagulation patient.
8. system of selection, it is the method that selection should give the disseminated intravascular coagulation patient of thrombomodulin, this method comprises the steps: to measure the antithrombin activity value in disseminated intravascular coagulation patient's the blood plasma, select this antithrombin activity value less than 50% disseminated intravascular coagulation patient, judge that this patient is the disseminated intravascular coagulation patient that should give thrombomodulin.
9. the Therapeutic Method of a disseminated intravascular coagulation and/or improvement method, it comprises the step that the antithrombin activity value in the blood plasma is given thrombomodulin less than 50% disseminated intravascular coagulation patient.
10. the therapeutic agent of a disseminated intravascular coagulation and/or improving agent, it is to be the medicine of effective ingredient with the thrombomodulin, this medicine is used for being applied to the disseminated intravascular coagulation patient after the antithrombin activity value of measuring blood plasma.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006274573 | 2006-10-06 | ||
| JP274573/2006 | 2006-10-06 | ||
| PCT/JP2007/069560 WO2008044631A1 (en) | 2006-10-06 | 2007-10-05 | Therapeutic and/or ameliorating agent for disseminated intravascular coagulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101522206A true CN101522206A (en) | 2009-09-02 |
| CN101522206B CN101522206B (en) | 2013-03-27 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007800368187A Active CN101522206B (en) | 2006-10-06 | 2007-10-05 | Therapeutic and/or ameliorating agent for disseminated intravascular coagulation |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US20100152106A1 (en) |
| EP (1) | EP2062589A4 (en) |
| JP (1) | JP5579385B2 (en) |
| KR (1) | KR20090051777A (en) |
| CN (1) | CN101522206B (en) |
| AU (1) | AU2007305550B2 (en) |
| BR (1) | BRPI0720158A2 (en) |
| CA (1) | CA2665691A1 (en) |
| CO (1) | CO6160332A2 (en) |
| HK (1) | HK1130209A1 (en) |
| IL (1) | IL197509A (en) |
| MX (1) | MX2009003384A (en) |
| MY (1) | MY148565A (en) |
| NZ (1) | NZ575632A (en) |
| RU (1) | RU2433829C2 (en) |
| UA (1) | UA97961C2 (en) |
| WO (1) | WO2008044631A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102858978A (en) * | 2010-04-30 | 2013-01-02 | 旭化成制药株式会社 | High-purity soluble thrombomodulin and method for producing same |
| CN102858978B (en) * | 2010-04-30 | 2016-12-14 | 旭化成制药株式会社 | Soluble thrombomodulin of high purity and manufacture method thereof |
| CN112839669A (en) * | 2018-09-28 | 2021-05-25 | 旭化成制药株式会社 | Drugs for alleviating symptoms and/or inhibiting the onset of peripheral nerve disorders caused by anticancer agents |
| CN113301907A (en) * | 2018-10-22 | 2021-08-24 | 旭化成制药株式会社 | Drug for treating and/or improving sepsis associated with blood coagulation disorder |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216326A (en) * | 2008-11-12 | 2011-10-12 | 伊莱利利公司 | Compositions and methods of use for thrombomodulin variants |
| RU2716492C1 (en) * | 2019-05-14 | 2020-03-12 | Федеральное Государственное Бюджетное Научное Учреждение "Федеральный Научно-Клинический Центр Реаниматологии И Реабилитологии" (Фнкц Рр) | Method of controlling neutrophil activation in in vitro model |
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| US5202421A (en) * | 1988-12-27 | 1993-04-13 | Mochida Pharmaceutical Co., Ltd. | Anticoagulant substance obtained from urine and process for the preparation thereof |
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| KR930008093B1 (en) * | 1990-08-03 | 1993-08-25 | 아사히가세이고오교 가부시끼가이샤 | New polypeptide and its composition |
| JPH05213998A (en) | 1990-08-03 | 1993-08-24 | Asahi Chem Ind Co Ltd | New polypeptide and medicinal composition containing the same as active ingredient |
| DE69132889T2 (en) | 1990-08-15 | 2002-08-29 | Paion Gmbh | SUPERIOR THROMBOMODULIN ANALOGS FOR PHARMACEUTICAL USE |
| JP3220174B2 (en) | 1990-12-12 | 2001-10-22 | 第一製薬株式会社 | Recombinant human thrombomodulin derivative |
| EP0641215B1 (en) | 1992-02-05 | 2004-04-21 | Paion GmbH | Protease-resistant thrombomodulin analogs |
| JPH05310787A (en) | 1992-05-01 | 1993-11-22 | Asahi Chem Ind Co Ltd | New polypeptide |
| JPH06205692A (en) | 1993-01-08 | 1994-07-26 | Asahi Chem Ind Co Ltd | Novel human thrombomodulin-resistant monoclonal antibody and method for highly sensitively measuring human thrombomodulin with the antibody |
| US5916874A (en) * | 1994-04-20 | 1999-06-29 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for treating liver injury |
| JP2824392B2 (en) | 1994-05-31 | 1998-11-11 | 旭化成工業株式会社 | Culture supernatant containing a peptide having an action of promoting the activation of protein C by thrombin |
| JP3745805B2 (en) | 1995-10-24 | 2006-02-15 | 日本ケミカルリサーチ株式会社 | Purification method of thrombomodulin |
| JP4157644B2 (en) | 1998-03-30 | 2008-10-01 | 旭化成ファーマ株式会社 | Method for producing high-purity soluble thrombomodulin |
| EP1476752A4 (en) * | 2002-02-27 | 2008-02-13 | Bio Merieux Inc | Method for diagnosing and monitoring hemostatic dysfunction, severe infection and systematic inflammatory response syndrome |
| JP4460443B2 (en) * | 2002-05-01 | 2010-05-12 | バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト | Novel tissue factor targeted antibodies as anticoagulants |
-
2007
- 2007-10-05 MY MYPI20091065A patent/MY148565A/en unknown
- 2007-10-05 BR BRPI0720158-3A2A patent/BRPI0720158A2/en not_active Application Discontinuation
- 2007-10-05 MX MX2009003384A patent/MX2009003384A/en active IP Right Grant
- 2007-10-05 EP EP07829298A patent/EP2062589A4/en not_active Withdrawn
- 2007-10-05 WO PCT/JP2007/069560 patent/WO2008044631A1/en active Application Filing
- 2007-10-05 JP JP2008538700A patent/JP5579385B2/en active Active
- 2007-10-05 CN CN2007800368187A patent/CN101522206B/en active Active
- 2007-10-05 RU RU2009117253/15A patent/RU2433829C2/en active
- 2007-10-05 NZ NZ575632A patent/NZ575632A/en unknown
- 2007-10-05 CA CA002665691A patent/CA2665691A1/en not_active Abandoned
- 2007-10-05 US US12/444,342 patent/US20100152106A1/en not_active Abandoned
- 2007-10-05 UA UAA200904468A patent/UA97961C2/en unknown
- 2007-10-05 KR KR1020097006989A patent/KR20090051777A/en not_active Ceased
- 2007-10-05 AU AU2007305550A patent/AU2007305550B2/en active Active
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2009
- 2009-03-10 IL IL197509A patent/IL197509A/en active IP Right Grant
- 2009-03-20 CO CO09029277A patent/CO6160332A2/en unknown
- 2009-11-05 HK HK09110256.9A patent/HK1130209A1/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102858978A (en) * | 2010-04-30 | 2013-01-02 | 旭化成制药株式会社 | High-purity soluble thrombomodulin and method for producing same |
| CN102858978B (en) * | 2010-04-30 | 2016-12-14 | 旭化成制药株式会社 | Soluble thrombomodulin of high purity and manufacture method thereof |
| CN112839669A (en) * | 2018-09-28 | 2021-05-25 | 旭化成制药株式会社 | Drugs for alleviating symptoms and/or inhibiting the onset of peripheral nerve disorders caused by anticancer agents |
| CN113301907A (en) * | 2018-10-22 | 2021-08-24 | 旭化成制药株式会社 | Drug for treating and/or improving sepsis associated with blood coagulation disorder |
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2008044631A1 (en) | 2010-02-12 |
| BRPI0720158A2 (en) | 2014-05-20 |
| JP5579385B2 (en) | 2014-08-27 |
| CN101522206B (en) | 2013-03-27 |
| MY148565A (en) | 2013-04-30 |
| MX2009003384A (en) | 2009-04-08 |
| IL197509A0 (en) | 2011-08-01 |
| UA97961C2 (en) | 2012-04-10 |
| HK1130209A1 (en) | 2009-12-24 |
| CA2665691A1 (en) | 2008-04-17 |
| KR20090051777A (en) | 2009-05-22 |
| EP2062589A4 (en) | 2010-07-28 |
| IL197509A (en) | 2015-06-30 |
| NZ575632A (en) | 2011-12-22 |
| AU2007305550B2 (en) | 2010-09-30 |
| US20100152106A1 (en) | 2010-06-17 |
| CO6160332A2 (en) | 2010-05-20 |
| AU2007305550A1 (en) | 2008-04-17 |
| WO2008044631A1 (en) | 2008-04-17 |
| RU2009117253A (en) | 2010-11-20 |
| EP2062589A1 (en) | 2009-05-27 |
| RU2433829C2 (en) | 2011-11-20 |
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